ABSTRACT Type 1 Diabetes Mellitus (T1DM) results from T cell-mediated autoimmune destruction of insulin-producing beta cells. The recent increase in T1DM incidence has occurred in too short a time interval to be due to genetics alone. Non-genetic factors can influence phenotype through epigenetic changes, such as the removal of repressive H3K27me3 (trimethylated lysine 27 on histone 3) marks. These changes are catalyzed by specific epigenetic regulators; however, the identity of epigenetic regulators important in T1DM, and how they function to promote disease development, are not completely understood. We recently reported that UTX (Ubiquitously Transcribed TPR protein X-chromosome), a pleiotropic epigenetic regulator with H3K27me3 demethylase activity, is required for differentiation of T follicular helper (Tfh) cells, a diabetogenic CD4+ T cell subset. Additionally, our data demonstrate that nonobese diabetic (NOD) mice with T cell-specific deletion of UTX (NOD- UTXTCD mice) are protected from T1DM development and have fewer Tfh cells in pancreatic lymph nodes. Thus, we hypothesize that UTX promotes T1DM development by removing repressive H3K27me3 marks at Tfh- associated loci to increase pathogenic Tfh numbers and function. To test this hypothesis, we will: i) define whether Tfh cell deficiency underlies diabetes protection in NOD-UTXTCD mice; ii) test whether UTX's demethylase function is required for T1DM development; and iii) identify the stage of diabetes development that requires UTX function. Completion of these Aims will provide fundamental insight into how UTX, and the pathways it regulates, may be therapeutically targeted to prevent and/or reverse T1DM. Since a small molecule inhibitor of H3K27me3 demethylation is available, the potential is high for near-term translation of these findings to the clinical realm. Moreover, multiple autoimmune conditions are mediated by Tfh cells and/or influenced by epigenetic changes, so that findings from this grant proposal have the potential to impact a range of autoimmune diseases beyond T1DM.